Mutations in the elastin gene (ELN) cause an obstructive vascular disease, supravalvular aortic stenosis (SVAS). We propose to study the role of ELN in vascular development and disease with the long term goal of improving therapy. The first aim of this proposal is to generate mice heterozygous and homozygous for ELN mutations using homologous recombination. We have produced mice with ELN deletions (ELN plus/minus and ELN minus/minus) and will generate mice harboring ELN truncations (ELN +/tr and ELN tr/tr). These mice model the common mutations associated with SVAS. The second aim is to characterize the cellular and molecular mechanisms of vascular pathology in these mice. We hypothesize that elastin has at least two functions in the vascular system. One is to regulate cell growth and differentiation during early vascular development, while a second is structural. Our preliminary data indicate that ELN minus/minus mice have severe obstructive vascular disease at birth. We expect these mice to be critical for examining the effect of elastin on early vascular development. By contrast, truncated elastin may effect elastic fiber structure. We expect that mice harboring the ELN truncation will be important for studying the structural role of elastin in the vasculature. The cellular pathogenesis of ELN mutations will be defined using gross, light and electron microscopic techniques. The onset, progression, and tissue distribution of pathology will be used to distinguish between the possible cellular mechanisms. We will then define molecular mechanisms using Northern, metabolic labeling, immunohistochemical, and functional analyses. The third aim is to develop a mouse model of complex vascular disease. Our preliminary data indicate that ELN plus/minus mice have subtle elastic fiber abnormalities but no obstructive vascular disease. Our preliminary data indicate that ELN plus/minus mice have subtle elastic fiber abnormalities but no obstructive vascular disease. We hypothesize that these abnormalities will exacerbate vascular pathology resulting from hypertension. To test this hypothesis, we will breed ELN plus/minus mice with mice harboring mutations that cause salt-sensitive hypertension (atrial natriuretic peptide deficient mice) and characterize the progeny. The fourth aim is to define the effect of therapeutic and dietary modulation of ELN expression on vascular disease. We hypothesize that the severity of vascular disease in mice harboring ELN mutations will be sensitive to agents that modulate ELN expression. We will test this hypothesis in tow ways. First, we will use maternal gene therapy to enhance fetal elastogenesis; this therapy should prevent or delay on onset of disease. Second, we will determine if vitamin D fortification reduces functional elastogenesis and accelerates vascular disease in ELN mutant mice.